This invention relates to metallotetrapyrrolic compounds having phototherapeutic properties utilizable in photodynamic therapy for photodetection and phototherapy of target tissues.
Photodynamic therapy (xe2x80x9cPDTxe2x80x9d) is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, normal tissues or pathogens. PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light. The photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen species. The interaction of the cytotoxic oxygen species with tissues in which the photosensitizer is localized causes a modification of the tissue, resulting in a desired clinical effect. The tissue specificity of the resultant phototoxic damage is determined largely, although not entirely, by the relative concentrations of the photosensitizer in each tissue at the time of exposure to the photoactivating light. The method of light delivery is also an important therapeutic factor.
Following systemic administration, many photosensitizers accumulate to varying degrees within tissues depending on the pharmacokinetic and distribution profile of the photosensitizing compound and the cell types comprising the tissues. The chemical factors that enable certain photosensitizers to accumulate at a target site to a greater degree than other photosensitizers is not well understood. In addition, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others is not well understood either. It is clear, however, that each photosensitizer has its own distribution and pharmacokinetic properties within different tissues and these properties determine the relative usefulness of the drug for the desired therapy. Currently, rigorous screening and biological evaluation in appropriate model systems is required to identify suitable photosensitizers that display the characteristics necessary within the diseased or target tissues for an effective therapy.
An emerging clinical role for photodynamic therapy is in the treatment of proliferative cardiovascular diseases such as atherosclerosis, restenosis and vein graft disease. Atherosclerosis is a disease that causes thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions of raised fibrous plaque that form within the vessel lumen. The plaques are most prevalent in, but not limited to, abdominal aorta, coronary arteries and carotid arteries and increase progressively with age. Intravascular ultrasound in man has shown that the plaque has a dome-shaped, opaque, glistening surface that protrudes into the lumen of the vessel. A lesion will typically consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits, necrotic tissue, thrombosis and fibrin. The occlusion of vessel lumen caused by the plaque leads to reduced blood flow, higher blood pressure and ultimately ischemic heart disease, if untreated.
The treatment of coronary atherosclerosis presently consists of pharmacological drug therapy, bypass surgery, percutaneous angioplasty and/or stent deployment. Drug therapy is primarily directed towards the control of hypertension (with vasodilators, diuretics, anti-adrenergic agents, angiotensin converting enzyme inhibitors etc) or stabilization of the plaque by lowering circulating lipid levels (with statins). The goal of the drug therapy is to return the patient""s arterial blood pressure and circulating cholesterol to normal levels and thereby reduce the stress on the patient""s heart, kidneys and other organs. Unfortunately, in some cases drug therapy can have side effects and does not control progressive or acute atherosclerosis.
In the more serious instances of coronary atherosclerosis, a thoracic bypass surgery may be performed, where a vein, usually from the patient""s leg, is used to bypass the occluded coronary artery. One end of the vein is attached to the aorta, and the other end is attached to the occluded vessel just beyond the obstruction. Although bypass surgery has become an accepted surgical procedure, it can present substantial morbidity risks, is expensive and generally requires extended hospital care. Moreover, the procedure is often limited to proximal vessels to the heart and the long-term prognosis is less than satisfactory. Roughly five percent of bypass grafts can be expected to occlude each year following the operation and the native vessel can also re-occlude as well, necessitating repeat procedures.
Percutaneous transluminal angioplasty (PTA) consists of balloon expansion of vessels to dilate areas of obstruction and has been used since the late 1980""s in the treatment of atherosclerotic coronary and peripheral vascular occlusive disease. Advances in catheter design have allowed more complex and distal stenoses and occlusions of coronary vessels to be treated with PTA. While this endovascular procedure displays excellent immediate revascularization of treated vessels and has gained acceptance as a less invasive alternative to bypass surgery, balloon angioplasty simply redistributes the atherosclerotic stenoses. It has also been determined that in some cases acute closure of the vessel after PTA and accelerated arteriosclerosis, or restenosis (re-occlusion) occurred as often as 40% within 6 months post-procedure. These re-occlusions further increase both as a function of the number of lesions treated and the time post-angioplasty.
Restenosis is the vessel""s natural healing response that typically occurs in direct proportion to the magnitude of the balloon angioplasty injury. The exact mechanisms responsible for the restenotic process are not fully understood and thus it is not surprising that at present there are no proven clinical therapies to prevent it. Nevertheless, recent studies in man and animals have shown that two events, intimal thickening and abnormal geometric remodeling, occur following PTA. Indeed, intravascular ultrasound and pathologic studies suggest that, in man, intimal thickening and vessel remodeling are responsible for approximately one-third and two-thirds of the total lumen loss, respectively. Intimal thickening involves the recruitment of vascular smooth muscle cells (VSMC) and perhaps advential myofibroblasts to the intima, where they proliferate and secrete an extracellular matrix. Stent deployment (metal scaffolding used to open vessels) is the only intervention that helps to reduce the effects of the vessel remodelling component of restenosis. However, while stents hold an artery open and significantly reduce acute closurexe2x80x94restenosis rates have been reduced with stents from 40% to 20-35%xe2x80x94it is clear that stents have not eliminated the problem.
Neointimal hyperplasia, i.e., new tissue growth through the sides of the stents, has created a new problem, in-stent restenosis. Interventional cardiologists have tried to remove this proliferative tissue with rotational and directional atherectomy, cutting balloons, eximer lasers, and deployment of another stent (stent sandwich), but none of these has shown to be effective. It is estimated that 1.8 million coronary interventions alone (0.36 million PTA and 1.45 million stent procedures) are performed worldwide each year, so a method of reducing neointima formation remains an important goal. Anti-restenosis treatments have focused on arresting the cell replication cycle and the proliferation of VSMC. A number of gene therapy approaches have been used unsuccessfully to interfere with VSMC proliferation including the use of antisense involved in cell proliferation (e.g. c-myc), and the use of adenovirus to increase nitric oxide synthase and thereby increase nitric oxide, an inhibitor of VSMC proliferation. Poor delivery of the gene therapy to the target vessel and immune reactions to some delivery vectors, however, have been major drawbacks for this method.
Researchers have looked to cancer treatments for ideas and ionizing radiation (brachytherapy) and stents coated with anti-cancer drugs have recently been identified as treatment options. At present, the use of drug coated stents has been restricted to animal studies and the few reports of human therapy appear to confirm the feasibility of the procedure. However, the best way to truly understand the vascular effect of drug-coated stents is to conduct long term studies well after the drug is completely eluted from the stent because it may be associated with inflammation and fibrin deposition, as seen in some animal models. Several devices are now available for applying radiation to recurrent narrowings within coronary stents or in-stent restenoses. However, a study recently failed to show the effectiveness of beta radiation (Beta-Cath system clinical trial; Novoste, 2001, Kuntz, et al, J. American College of Cardiology, Febuary, 2001) in preventing renarrowing of de novo coronary lesions, i.e., lesions that have not yet been treated with either PTA or stenting. Moreover, in animal and human studies it has been found that if the dose of radiation is too high, there is no healing of the lumenal endothelial lining of the intima resulting in an increased risk of late-onset thrombosis. Conversely, if the dose is too low, then restenosis and arteriosclerosis could actually be accelerated. Other technologies are being developed including cryotherapy using hypothermia, for example. These products all have technical challenges. The efficacy in animal models to date has been unimpressive and each is still far from commercialization.
There exists a need for better methods for treatment of atherosclerosis and restenosis. When considering a therapy to treat or prevent restenosis, one must consider the steps in the complicated biologic cascade with which the therapeutic agent (e.g., photosensitizer) is designed to interfere, where the target cells will be when the proposed treatment is to be applied, and what the least traumatic and most efficient route of administration of that agent is for the specific problem to be treated. The ultimate objective of any therapy is to inhibit neointima formation while also promoting the controlled healing of the vessel wall.
Recently, vascular photodynamic therapy has shown promise for the prevention of injury-induced neointimal hyperplasia in animal studies and has entered phase I/II clinical trials in man (Lutetium texaphyrin; Pharmacyclics). In this study, a photosensitizer was administered intravenously or locally to a patient and, after a predetermined time that depends on the optimal localization of the drug, the photosensitizer reached the target vascular lesion and light of an appropriate wavelength was used to activate the drug.
Several photosensitizers have been developed largely for use in oncological applications, and have also been examined in the cardiovascular field, mostly in preclinical animal models. Such photosensitizers include Photofrin, 5-amino-levulinic acid (protoporphyrin IX precursor), tin ethyl etiopurpurin (SnET2), Visudyne(copyright) (Benzoporphyrin derivative), Antrin(copyright), Optrin(copyright) (Lutetium texaphyrin), mono-aspartyl chlorin e6 (MACE), and pheophorbide PH1126. All of these synthetic compounds were designed specifically for the treatment of solid tumors. Specifically, many of these compounds were designed to have large absorptions in the 620-740 nm range so as to optimize the photoactivation of the drug with a wavelength that will penetrate to the greatest depths possible in all tissue types. In particular, these drugs were designed to absorb outside of the blood absorption profile, thus ensuring efficient photoactivation in most tissue types.
The excitation light source for PDT (usually diode lasers or dye lasers) has historically been matched to the far-red absorption bandwidth of the photosensitizer to maximize light penetration through blood in the arteries. Indeed, the present inventors believe that all the tetrapyrrolic photosensitizers used in cardiovascular indications have been designed for long wavelength absorption of light to address this perceived issue. The light is then delivered to the treatment site via radially emitting fibers, often enclosed in balloon catheters (with a variety of designs), to exclude as much of the blood as possible.
Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic, restenotic lesions and vein graft intimal hyperplasia) is fueled by more effective second-generation photosensitizers that are designed specifically for cardiovascular indications and technological advances in endovascular light delivery catheters. These molecules may be used adjunctively with other debulking procedures. This enthusiasm revolves around at least four significant attributes of light-activated therapy: a) the putative selectivity and safety of photoangioplasty, b) the potential for atraumatic and effective stabilization of atheromatous plaque through a biological mechanism, c) the postulated capability to reduce or inhibit restenosis using minimally invasive clinically relevant interventional techniques, and d) the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions.
While several of the photosensitizers described above have been used to treat atheromatous plaques and some are able to display some inhibition of intimal hyperplasia in animal models, many if not all have characteristics that will limit the usefulness of these drugs in a clinical setting. One particular concern is the half-life of the photosensitizer. A photosensitizer delivered systemically with a long half-life (CASPc, Photofrin, SnET2) may have phototoxic side effects if exposed to direct light, within days of the procedure.
A second even more pressing concern that has to date escaped many of the investigators testing new photosensitizers in cardiovascular disease is photochemically induced damage to xe2x80x9cnormalxe2x80x9d myocardial tissue surrounding the artery due to non-selective photosensitizer uptake and long depths of light penetration, which activates the photosensitizer in the myocardial tissue. Historically, it has been believed that attenuation of the photosensitizer excitation light by blood would inhibit the use of wavelengths of light shorter than 600 nm in the cardiovascular field. This may have been true several years ago when balloon catheter technology in PDT was not as advanced as it is today. New endovascular light ballon catheters, however, can remove most of the blood from the treatment area. This advance enables the use of short wavelengths of light that historically may have been attenuated by blood.
The use of wavelengths of light lower than 600 nm offers significant advantages in PDT because such wavelengths have penetration characteristics that deliver the PDT effect to the target sites (media and adventicia layers of the vessel) and not to myocardial tissue. Thus, effective therapy can be afforded at the target site, while deeper tissues are shielded from a PDT response by blood absorption within these tissues. Previously reported cardiovascular experiments performed to date on tetrapyrrolic molecules have been done at wavelengths  greater than 620 nm. Experiments that we have performed in pig arteries with new photosensitizer candidates at light activation  greater than 600 nm have resulted in unacceptable levels of damage to myocardial or cardiac muscle tissue surrounding the treatment area. This has major clinical implications to patients with existing ischemic myocardial or muscle tissue due to poor artery perfusion. Attempts to lower the light dosimetry in order to limit treatments to the target tissue (media/intima) leads to long treatment times and less efficacy. In addition, long treatment times in the artery exposes the patient to additional risks with inflation and deflation of the balloon devices. Importantly, the present inventors have demonstrated in pig arteries that effective treatment depths can be obtained with shorter wavelengths of light, while sparing underlying tissue damage.
Thus, in our opinion, long wavelength absorbing molecules ( greater than 600 nm), unless highly selective to target myocardial and intimal tissues (which has not to date been reported with any photosensitizer in cardiovascular tissues), may cause unacceptable normal cardiac tissue damage. Therefore, it would appear that activation of lutetium texaphyrin, BPD-MA, MACE, CASPc, SnET2, and pheophorbide PH-II26 with red light may be of limited use in the treatment of cardiovascular disease, as all of these compounds have low energy xe2x80x9credxe2x80x9d absorbtions by design ( greater than 600 nm). It should be noted also that chlorins, phthalocyanines and texaphyrin type photosensitizers in general have little absorption in the 500-600 nm regions, and thus may be suboptimal with regard to light activation at green and yellow wavelengths in cardiovascular tissues. In addition, protoporphyrin IX and photofrin do not display absorption maximas at 532 nm, thus they may be inefficient at absorbing treatment light at this wavelength and have very low molar extinction coefficients at 575 nm (xcx9c7000 cmxe2x88x921/Mxe2x88x921). Furthermore, because long wavelength photosensitizers by design have red absorption peaks, operating room lighting in an emergency situation may cause serious photosensitivity in light exposed tissues. Attempts to use red light filters on operating room lights to minimize tissue damage due to the red light penetration results in poor tissue contrast and sub-optimal lighting conditions, making surgical procedures under these conditions extremely difficult, if not impossible. Optical clarity is much better at shorter wavelengths (500-600 nm) where the depth of light peneration is limited to a few mm of tissue penetration.
Another important consideration in the design of cardiovascular photosensitizers that absorb at shorter wavelengths is that they must have absorptions at wavelengths where excitation light devices emit maximally. At 532 nm, efficient inexpensive diode lasers are available. At other wavelengths (besides blue) less than 600 nm-only dye lasers exist to supply enough light power to undertake a PDT treatment. These are particularly useful at 580 nm. Blue lasers are available, and even though most of the photosensitizers that have been used in cardiovascular diseases have blue absorptions, the light output of these devices currently limits their applicability to high power light treatments. Also, blood attenuation of light in the blue region of the spectrum (350 to 460 nm) is significantly greater than in the green/yellow region (500 to 600 nm). Thus, photosensitizers being activated in the blue region may suffer larger therapeutic inconsistencies if small amounts of blood are present within the vessel treatment area. Should high power blue lasers come onto the market, it may be possible (although difficult) to overcome significant blood attenuation in the blue region, and perhaps effect a desired therapy.
For these reasons, there is a real need for xe2x80x9cshorter wavelengthxe2x80x9d absorbing photosensitizer agents that do not display red absorptions, that are cleared rapidly from normal tissues (especially skin), and that are effective in the treatment of intimal hyperplasia, atheromatous plaques, peripheral artery disease, and vein graft hyperproliferation. Additionally, as more disease indications are realized, shorter wavelength light may be equally important in other PDT applications that only require short wavelength excitation to effect a therapy. Such applications may be in hollow organ disease (for example, lung cancers and barrets esophagus), and in diseases of the skin (for example, psoriasis, actinic keratosis, and acne vulgaris).
The present invention is directed to certain metallated photosensitizers that have shown excellent efficacy in advanced animal model systems as well as preferred uptake in the target tissue, with excellent clearance characteristics and low toxicity. These compounds are expected to be useful not only in cardiovascular disease indications, but also for indications in dermatology, oncology, ophthalmology, urology, and in dentistry.
The present invention overcomes the disadvantages of the prior art by providing novel metallated functionalized phototherapeutic agents of the tetrapyrrolic type, which display excellent uptake into cardiovascular tissues of interest, show low systemic toxicity and low myocardial tissue toxicity on light activation, and are cleared rapidly from skin and other tissues. These phototherapeutic agents are based on tetrapyrrolic ring systems such as the porphyrins.
We have additionally discovered that a single chemical modification of tetrapyrrolic compounds involving the coordination of a gallium ion into the central cavity of tetrapyrrolic compounds to produce a gallium tetrapyrrolic complex, unexpectedly markedly enhances the uptake and biological efficacy of the compounds as photosensitizers for PDT of cardiovascular diseases when compared to the corresponding tetrapyrrolic compounds having other metal types coordinated to their central cavity. Additionally, tetrapyrrolic macrocycles that coordinate gallium when administered topically or systemically, show unexpected skin tissue responses, such as hair growth stasis and positive skin remodelling (deposition of collagen) following treatment with light. These effects are not observed with other metallotetrapyrrolic macrocycles. Therefore, a preferred embodiment of the invention is directed to certain tetrapyrrolic compounds metallated with gallium.
The invention also provides new methods of treating cardiovascular diseases with PDT utilizing light at shorter wavelengths with the new metallated porphyrins of the invention, thus minimizing damage to the myocardial or muscle tissue.
The invention further provides new photosensitizers that may be used in short wavelength applications in photodynamic therapy to treat diseases other than cardiovascular diseases.
To achieve these and other advantages, and in accordance with the purpose of the invention, as embodied and broadly described herein, the present invention, in one aspect, provides phototherapeutic compositions of metallotetrapyrrolic compounds of formula I which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases: 
In formula I, R1-R12 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CHxe2x95x90CH(aryl), CHxe2x95x90CHCH2N(CH3)2, or a functional group of molecular weight of less than about 100,000 daltons; CHxe2x95x90CHCH2N+(CH3)3A, CHxe2x95x90N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, CH(CH3)O-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl; where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R13, where R13 is selected from H, a physiologically acceptable counter ion, a C1-C20 straight or branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR14, where R14 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R15, (CHX)nCO2R15, or (CX2)nCO2R15, where X is a halogen and R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
CONH(R16), CONHNH(R16), CO(R16), CON(R16)2, CON(R16)(R17) (CH2)nCONH(R16), (CH2)nCON(R16)2, (CH2)nCOR16, (CH2)nCON(R16)(R17), (CX2)nCONH(R16), (CX2)nCON(R16)2, (CX2)nCON(R16)(R17), (CX2)nCOR16, (CH2)nCONHNH(R16), (CX2)nCONHNH(R16), (CHX)nCONH(R16), (CHX)nCONHNH(R16), (CHX)nCO(R16), (CHX)nCON(R16)2, or (CHX)nCON(R16)(R17), where X is a halogen and R16 and R17 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
S(R18), (CH2)nS(R18), (CH2)nNH(R18), (CH2)nNHNH(R18), (CH2)nN(R18)2, (CH2)nN(R18)(R19), or (CH2)nN(R18)(R19)(R20)+A, where R18, R19 and R20 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R18) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R18, R19 and R20 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR21, (CH2)nPO(OR21)2, (CH2)nPO2R21, or (CH2)nPOR21 where R21 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR22, or (CH2)nNHNHCOR22, where R22 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R23, SO2NHR23, SO2N(R23)2, SO2NHNHR23, SO2N(R23)(R24) or SO2R23, where R23 and R24 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR22 can also be an amino acid, an amino acid salt, an amino acid ester residue, and an amino acid amide residue;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R4-R5, R7-R8, R10-R11, R2-R3, R5-R6, R8-R9, and R11-R12 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
In formula I, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+, wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IA: 
In formula IA, R1 and R2 can be the same or different and can be selected from:
CO2R3, where R3 is selected from H, a physiologically acceptable salt, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
CONH(R4), CONHNH(R4), CON(R4)2, COR4, or CON(R4)(R5), where R4 and R5 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where R6 is selected from a C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R7, (CHX)nCO2R7, or (CX2)nCO2R7, where X is a halogen and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R8), (CH2)nCO(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2, (CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CHX)nCONH(R9), (CHX)nCONHNH(R9), (CHX)nCON(R9)2, or (CHX)nCON(R8)(R9), where X is a halogen, and R8 and R9 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R10), (CH2)nS(R10), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(R10)2, (CH2)nN(R10)(R11), or (CH2)nN(R10)(R11)(R12)+A, where R10, R11 and R12 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, an amino acid or a salt, ester or amide thereof (provided xe2x80x94NH(R10) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R10, R11 and R12 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4 and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR13, (CH2)nPO(OR13)2, (CH2)nPO2R13, or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR14 or (CH2)nNHNHCOR14, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, SO2NHR15, SO2N(R15)2, SO2NHNHR15, SO2N(R15)(R16) or SO2R15, where R15 and R16 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
In formula IA, M is preferably Ga3+, wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion, but M in formula IA can also be selected from Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Mg2+, Zn2+ either with or without a physiologically acceptable charge balancing counter ion.
In another preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IB: 
In formula IB, R1 and R2 can be the same or different and can be selected from H; CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R4 can be the same or different and are selected from:
CO2R5, where R5 is selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons;
CONH(R6), CONHNH(R6), CON(R6)2, or CON(R6)(R7), where R6 and R7 can be the same or different and can be selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R9, (CHX2)nCO2R9, or (CX2)nCO2R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCON(R10)(R11), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(R11), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(R10)(R11), where X is a halogen, and R10 and R11 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, also where NH(R10) is part of an amino acid, an amino acid salt, an amino acid ester, or an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R12), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(R13), (CH2)nN(R12)(R13)(R14)+A, where R12 and R13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided xe2x80x94NH(R12) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R12, R13 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR15, (CH2)nPO(OR15)2, (CH2)nPO2R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R16 is a a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, SO2NHR17, SO2N(R17)2, SO2NHNHR17, SO2N(R17)(R18) or SO2R17, where R17 and R18 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons.
In formula 1B, M is Ga3+, wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion.
In another aspect of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula II that may be useful as photosensitizers in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases: 
In formula II, R1 to R11 can be the same or different and can be selected from:
H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CHxe2x95x90CH(aryl), CHxe2x95x90CHCH2N(CH3)2, or a functional group of molecular weight less than about 100,000 daltons; CHxe2x95x90CHCH2N+(CH3)3A, CHxe2x95x90N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion, CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, CH(CH3)O-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R12, where R12 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR13, where R13 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R14, (CX2)nCO2R14, or (CHX)nCO2R14, where X is a halogen and R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R15), CONHNH(R15), CO(R15), CON(R15)2, CON(R15)(R16), (CH2)nCONH(R15), (CH2)nCONHNH(R15), (CH2)nCON(R15)2, (CH2)nCOR15, (CH2)nCON(R15)(R16), (CX2)nCONH(R15), (CX2)nCONHNH(R15), (CX2)nCON(R15)2, (CX2)nCON(R15)(R16), (CX2)nCOR15, (CHX)nCONH(R15), (CHX)nCONHNH(R15), (CHX)nCON(R15)2, (CHX)nCON(R15)(R16), or (CHX)nCOR15, where X is a halogen and R15 and R16 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R17), (CH2)nS(R17), (CH2)nNH(R17), (CH2)nNHNH(R17), (CH2)nN(R17)2, (CH2)nN(R17)(R18), or (CH2)nN(R17)(R18)(R19)+A, where R17, R18 and R19 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R17) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R17, R18 and R19 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR20, (CH2)nPO(OR20)2, (CH2)nPO2R20, or (CH2)nPOR20 where R20 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR21 or (CH2)nNHNHCOR21, where R21 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R22, SO2NHR22, SO2NHNHR22, SO2N(R22)2, SO2N(R22)(R23) or SO2R22, where R22 and R23 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHA can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue, and n is an integer between 0 and 4;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R3-R4, R6-R7, R9-R10, R4-R5, R5-R6, R8-R9, R9-R10, R11-R12 and R12-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
In formula II, M is a diamagnetic or paramagnetic photoactive metal ion preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+, wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IIA 
In formula IIA, R1-R6 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CHxe2x95x90CH(aryl), CHxe2x95x90CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CHxe2x95x90CHCH2N+(CH3)3A, CHxe2x95x90N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, or CH(CH3)O-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R7, where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R9, (CHX)nCO2R9, or (CX2)nCO2R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(R10)(R11), (CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(R11), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(R11), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, (CHX)nCON(R10)(R11), or (CHX)nCOR10, where X is a halogen, and R10 and R11 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R12), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(R13), or (CH2)nN(R12)(R13)(R14)+A, where R12, R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R13) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R12, R13 and R14 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR15, (CH2)nPO(OR15)2, (CH2)nPO2R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, SO2NHR17, SO2NHNHR17, SO2N(R17)2, SO2N(R17)(R18) or SO2R17, where R17 and R18 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR17 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
In formula IIA, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. Additionally, and in accordance with the present invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula III which may be useful in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases: 
In formula III, R1 to R10 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CHxe2x95x90CH(aryl), CHxe2x95x90CHCH2N(CH3)2, or a functional group having a molecular weight of about 100,000 daltons; CHxe2x95x90CHCH2N+(CH3)3A, CHxe2x95x90N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, or CH(CH3)O-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R11, where R11 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR12, where R12 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R13, (CHX)nCO2R13, or (CX2)nCO2R13, where X is a halogen, and R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R14), CONHNH(R14), CO(R14), CON(R14)2, CON(R14)(R15), (CH2)nCONH(R14), (CH2)nCONHNH(R14), (CH2)nCON(R14)2, (CH2)nCOR14, (CH2)nCON(R14)(R15), (CX2)nCONH(R14), (CX2)nCONHNH(R14), (CX2)nCON(R14)2, (CX2)nCON(R14)(R15), (CX2)nCOR14, (CHX)nCONH(R14), (CHX)nCONHNH(R14), (CHX)nCON(R14)2, (CHX)nCON(R14)(R15), or (CHX)nCOR14, where X is a halogen, and R14 and R15 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R16), (CH2)nS(R16), (CH2)nNH(R16), (CH2)nNHNH(R16), (CH2)nN(R16)2, (CH2)nN(R16)(R17), or (CH2)nN(R16)(R17)(R18)+A, where R16, R17 and R18 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R16) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R16, R17 and R18 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR19, (CH2)nPO(OR19)2, (CH2)nPO2R19, or (CH2)nPOR19 where R19 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR20 or (CH2)nNHNHCOR20, where R20 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R21, SO2NHR21, SO2NHNHR21, SO2N(R21)2, SO2N(R21)(R22) or SO2R21, where R21 and R22 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR21 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R3-R4, R6-R7, R8-R9, R4-R5, R5-R6, R9-R10, and R10-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
In formula III, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IIIA: 
In formula IIIA, R1, R2, R3, R4 can be the same or different and can be selected from: a functional group of less than about 100,000 daltons;
CO2R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where R6 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R7, (CHX)nCO2R7, or (CX2)nCO2R7, where X is a halogen, and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R8), CONHNH(R8), CO(R8), CON(R8)2, CON(R8)(R9), (CH2)nCONH(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2, (CH2)nCOR8, (CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCONHNH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CX2)nCOR8, (CHX)nCONH(R8), (CHX)nCONHNH(R8), (CHX)nCON(R8)2, (CHX)nCON(R8)(R9), or (CHX)nCOR8, where X is a halogen, and R8 and R9 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R10), (CH2)nS(R10), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(R10)2, (CH2)nN(R10)(R11), or (CH2)nN(R10)(R11)(R12)+A, where R10, R11 and R12 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R10) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R10, R11 and R12 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR13, (CH2)nPO(OR13)2, (CH2)nPO2R13, or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR14 or (CH2)nNHNHCOR14, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, SO2NHR15, SO2NHNHR15, SO2N(R15)2, SO2N(R15)(R16) or SO2R15, where R15 and R16 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR15 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons.
In formula IIIA, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. Additionally, and in accordance with the present invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IV which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases: 
In formula IV, R1-R8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CHxe2x95x90CH(aryl), CHxe2x95x90CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CHxe2x95x90CHCH2N+(CH3)3A, CHxe2x95x90N(alkyl)2A, or N(alkyl)3+A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), CO2H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)O-alkyl, CH(CH3)O-alkoxy, or CH(CH3)O-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R9, where R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR10, where R10 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R11, (CHX)nCO2R11, or (CX2)nCO2R11, where X is a halogen, and R11 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R12), CONHNH(R12), CO(R12), CON(R12)2, CON(R12)(R13), (CH2)nCONH(R12), (CH2)nCONHNH(R12), (CH2)nCON(R12)2, (CH2)nCOR12, (CH2)nCON(R12)(R13), (CX2)nCONH(R12), (CX2)nCONHNH(R12), (CX2)nCON(R12)2, (CX2)nCON(R12)(R13), (CX2)nCOR12, (CHX)nCONH(R12), (CHX)nCONHNH(R12), (CHX)nCON(R12)2, (CHX)nCON(R12)(R13), or (CHX)nCOR12, where X is a halogen, and R12 and R13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R14), (CH2)nS(R14), (CH2)nNH(R14), (CH2)nNHNH(R14), (CH2)nN(R14)2, (CH2)nN(R14)(R15), or (CH2)nN(R14)(R15)(R16)+A, where R14, R15 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided xe2x80x94NH(R14) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R14, R15 and R16 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR17, (CH2)nPO(OR17)2, (CH2)nPO2R17, or (CH2)nPOR17 where R17 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR18 or (CH2)nNHNHCOR18, where R18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R19, SO2NHR19, SO2NHNHR19, SO2N(R19)2, SO2N(R19)(R20) or SO2R19, where R19 and R20 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHA can also be an amino acid, an amino acid salt, an amino acid ester residue;
aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
A, B, C, and D can be the same or different and can be selected from N, CH, CR20, where R20 is selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional group of less than about 100,000 daltons.
In formula IV, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, In3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
In accordance with a preferred embodiment of the invention, the metallotetrapyrrolic compounds of the invention are derived by various procedures from naturally occurring cyclic tetrapyrroles. The naturally occuring cyclic tetrapyrrolic molecules have the basic ring structure shown in Table 1 herein and are particularly preferred as starting materials for the synthesis of compounds of formula I.
In another preferred embodiment of the invention, the metallotetrapyrrolic molecules of the invention are derived by the coupling of suitably substituted dipyrromethane, dipyrromethenes, biladienes, builirubins, pyrroles and functionalized aldehydes, or functionalized maleonitriles. These cyclic tetrapyrroles have the basic ring structure shown in Table 2, and are particularly preferred as starting materials for the synthesis of the compounds of formulae II-IV.
In accordance with another embodiment of this invention, there is provided a method for detection and treatment of cardiovascular tissue or other tissue abnormalities in a patient. The method comprises administering to the patient an effective amount of a metallotetrapyrrolic compound of the invention and exposing the tissue to light within the photoactivating spectrum of the particular tetrapyrrolic compound.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.